AU3480401A - C7 heterosubstituted acetate taxanes as antitumor agents - Google Patents

Abstract

Texanes having a heterosubstituted acetate substituent at C(7), a hydroxy substitutent at C(10), and a range of C(2), C(9), C(14), and side chain substituents.

Description

WO 01/57029 PCT/USO1/03600 1 C7 HETEROSUBSTITUTED ACETATE TAXANES AS ANTITUMOR AGENTS BACKGROUND OF THE INVENTION The present invention is directed to novel taxanes which have exceptional utility as antitumor agents. 5 The taxane family of terpenes, of which baccatin Ill and taxol are members, has been the subject of considerable interest in both the biological and chemical arts. Taxol itself is employed as a cancer chemotherapeutic agent and possesses a broad range of tumor-inhibiting activity. Taxol has a 2'R, 3'S configuration and the following structural formula: AcO

C

6

H

5 CONH 0 0 OH C6H 5 = 0" OH '' HO . BzfO 0 AcO 10 wherein Ac is acetyl. Colin et al. reported in U.S. Patent 4,814,470 that certain taxol analogs have an activity significantly greater than that of taxol. One of these analogs, commonly referred to as docetaxel, has the following structural formula: OH tBuOCONH 0 0 OH OH HO 0l. 15 AcO Although taxol and docetaxel are useful chemotherapeutic agents, there are limitations on their effectiveness, including limited efficacy against certain types of cancers and toxicity to subjects when administered at various doses. 20 Accordingly, a need remains for additional chemotherapeutic agents with improved efficacy and less toxicity.

WO 01/57029 PCT/US01/03600 2 SUMMARY OF THE INVENTION Among the objects of the present invention, therefore, is the provision of taxanes which compare favorably to taxol and docetaxel with respect to efficacy as anti-tumor agents and with respect to toxicity. In general, these taxanes 5 possess a heterosubstituted acetate substituent at C-7, a hydroxy substituent at C-10 and a range of C-3' substituents. Briefly, therefore, the present invention is directed to the taxane composition, per se, to pharmaceutical compositions comprising the taxane and a pharmaceutically acceptable carrier, and to methods of administration. 10 Other objects and features of this invention will be in part apparent and in part pointed out hereinafter. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS In one embodiment of the present invention, the taxanes of the present invention correspond to structure (1): 15

X

5 NH 0

R

10

R

9 x 3 rR9 H7 X3 01O, OH R14 HO= . R2 i0 OAc (1) wherein 20 R 2 is acyloxy;

R

7 is heterosubstituted acetate; R. is keto, hydroxy, or acyloxy;

R

1 is hydroxy;

R,

4 is hydrido or hydroxy; 25 X 3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, phenyl or heterocyclo; X. is -COX 10 , -C00X 1 0 , or -CONHX 1 0 ;

X

1 0 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo; Ac is acetyl; and 30 R 7 , R., and R 1 independently have the alpha or beta stereochemical configuration.

WO 01/57029 PCT/USO1/03600 3 In one embodiment, R 2 is an ester (R 2 aC(0)O-), a carbamate

(R

2 aR 2 NC(O)0-), a carbonate (R 2 aOC(O)O-), or a thiocarbamate (R 2 aSC(O)0-) wherein R 2 a and R 2 b are independently hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo. In a preferred embodiment, R 2 is an ester 5 (R 2 aC(0)O-), wherein R 2 a is aryl or heteroaromatic. In another preferred embodiment, R 2 is an ester (R 2 aC(0)O-), wherein R 2 a is substituted or unsubstituted phenyl, furyl, thienyl, or pyridyl. In one particularly preferred embodiment, R 2 is benzoyloxy. In one embodiment, R 7 is R 7 aC(0)0- wherein R 7 a is heterosubstituted 10 methyl, said heterosubstituted methyl moiety lacking a carbon atom which is in the beta position relative to the carbon atom of which R 7 a is a substituent. The heterosubstituted methyl is covalently bonded to at least one heteroatom and optionally with hydrogen, the heteroatom being, for example, a nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or halogen atom. The heteroatom may, in 15 turn, be substituted with other atoms to form a heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, oxy, acyloxy, nitro, amino, amido, thiol, ketals, acetals, esters or ether moiety. Exemplary R 7 substituents include

R

7 aCOO- wherein R 7 a is chloromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, or methylthiomethyl. 20 While R. is keto in one embodiment of the present invention, in other embodiments R, may have the alpha or beta stereochemical configuration, preferably the beta stereochemical configuration, and may be, for example, a- or P-hydroxy or a- or p-acyloxy. For example, when R. is acyloxy, it may be an ester (RgaC(0)O-), a carbamate (ReaRgbNC(0)0-), a carbonate (RgaOC(O)O-), or a 25 thiocarbamate (ReaSC(0)O-) wherein Rea and Rgb are independently hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo. If R. is an ester (ReaC(0)O-), Rga is or unsubstituted alkyl, or unsubstituted alkenyl, or unsubstituted aryl or or unsubstituted heternaromatic. Still mnm nrnfrnhlx' R- iOR n Pqter (R. C(0)(0-) WO 01/57029 PCT/USO1/03600 4 wherein the substituent(s) islare selected from the group consisting of heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester and ether moieties, but not phosphorous containing moieties. 5 Exemplary X 3 substituents include substituted or unsubstituted C2 to C8 alkyl, substituted or unsubstituted C2 to C alkenyl, substituted or unsubstituted C2 to C alkynyl, substituted or unsubstituted heteroaromatics containing 5 or 6 ring atoms, and substituted or unsubstituted phenyl. Exemplary preferred X 3 substituents include substituted or unsubstituted ethyl, propyl, butyl, cyclopropyl, 10 cyclobutyl, cyclohexyl, isobutenyl, furyl, thienyl, and pyridyl. Exemplary X. substituents include -COX 1 0 , -C00X 10 or -CONHX 1 wherein

X

1 0 is substituted or unsubstituted alkyl, alkenyl, phenyl or heteroaromatic. Exemplary preferred X. substituents include -COX 1 0 , -COOX 10 or -CONHXIO wherein X 1 . is (i) substituted or unsubstituted C1 to C alkyl such as substituted or 15 unsubstituted methyl, ethyl, propyl (straight, branched or cyclic), butyl (straight, branched or cyclic), pentyl (straight, branched or cyclic), or hexyl (straight, branched or cyclic); (ii) substituted or unsubstituted C2 to C alkenyl such as substituted or unsubstituted ethenyl, propenyl (straight, branched or cyclic), butenyl (straight, branched or cyclic), pentenyl (straight, branched or cyclic) or 20 hexenyl (straight, branched or cyclic); (iii) substituted or unsubstituted C2 to C8 alkynyl such as substituted or unsubstituted ethynyl, propynyl (straight or branched), butynyl (straight or branched), pentynyl (straight or branched), or hexynyl (straight or branched); (iv) substituted or unsubstituted phenyl, or (v) substituted or unsubstituted heteroaromatic such as furyl, thienyl, or pyridyl, 25 wherein the substituent(s) is/are selected from the group consisting of heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester and ether moieties, but not phosphorous containing moieties. In one embodiment of the present invention, the taxane corresponds to 30 structure 1, X. is -COX 1 wherein X 1 0 is phenyl or -COOX 1 0 wherein X 1 0 is t butoxycarbonyl, and R 7 is R 7 aC(O)O- wherein R 7 a is alkoxymethyl, preferably methoxymethyl or ethoxymethyl. In another embodiment of the present invention the taxane corresponds to structure 1, X 5 is -COX 1 0 wherein X 1 0 is phenyl or -COOX1 0 wherein X 1 0 is t-butoxycarbonyl, and R 7 is R 7 aC(0)O- wherein R 7 a is 35 acyloxymethyl, preferably acetoxymethyl.

WO 01/57029 PCT/USO1/03600 5 In another embodiment of the present invention, the taxane corresponds to structure 1, X 5 is -COX 1 0 wherein X 1 0 is phenyl or -COOXO wherein X 1 0 is t butoxycarbonyl, R 7 is R 7 ,C(0)O- wherein R 7 . is alkoxymethyl such as methoxymethyl or ethoxymethyl, or aryloxymethyl such as phenoxymethyl, and X 3 5 is heterocyclo. In another embodiment of the present invention the taxane corresponds to structure 1, X 5 is -COX 1 0 wherein X 1 0 is phenyl or -C00X 10 wherein X 1 0 is t-butoxycarbonyl, and R 7 is R 7 aC(O)O- wherein R 7 a is acyloxymethyl, preferably acetoxymethyl, and X 3 is heterocyclo. In one preferred embodiment, the taxanes of the present invention 10 correspond to structure (2):

X

5 NHO R1 0 Ry X3 O OH HO . . BzOAc 0 (2) wherein

R

7 is heterosubstituted acetate;

R

1 0 is hydroxy; 15 X 3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, or heterocyclo; X, is -COX 1 0 , -C00X 10 , or -CONHX 10 ; and X1 0 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo. For example, in this preferred embodiment in which the taxane corresponds to structure (2), R 7 may be R 7 aCOO- wherein R 7 , is heterosubstituted methyl, more 20 preferably heterosubstituted methyl wherein the heterosubsituents are selected from the group consisting of nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or halogen atoms, still more preferably heterosubstituted methyl wherein the heterosubstituent is alkoxy or acyloxy. While R 7 a is selected from among these, in one embodiment X 3 is selected from substituted or unsubstituted alkyl, alkenyl, 25 phenyl or heterocyclo, more preferably substituted or unsubstituted alkenyl, phenyl or heterocyclo, still more preferably substituted or unsubstituted phenyl or heterocyclo, and still more preferably heterocyclo such as furyl, thienyl or pyridyl. While R 7 a and X 3 are selected from among these, in one embodiment X, is selected from -COX 1 0 wherein X 1 0 is phenyl, alkyl or heterocyclo, more preferably WO 01/57029 PCT/USO1/03600 6 phenyl. Alternatively, while R 7 . and X 3 are selected from among these, in one embodiment X. is selected from -COX 10 wherein X 1 0 is phenyl, alkyl or heterocyclo, more preferably phenyl, or X, is -C00X 1 0 wherein X 1 0 is alkyl, preferably t-butyl. Among the more preferred embodiments, therefore, are 5 taxanes corresponding to structure 2 in which (i) X. is -COOX 1 0 wherein X 1 0 is tert butyl or X. is -COX 10 wherein X 10 is phenyl, (ii) X 3 is substituted or unsubstituted cycloalkyl, alkenyl, phenyl or heterocyclo, more preferably substituted or unsubstituted isobutenyl, phenyl, furyl, thienyl, or pyridyl, still more preferably unsubstituted isobutenyl, furyl, thienyl or pyridyl, and (iii) R 7 is alkoxyacetyl or 10 acyloxyacetyl. Taxanes having the general formula 1 may be obtained may be obtained by treatment of a p-lactam with an alkoxide having the taxane tetracyclic nucleus and a C-13 metallic oxide substituent to form compounds having a 0-amido ester substituent at C-13 (as described more fully in Holton U.S. Patent 5,466,834), 15 followed by removal of the hydroxy protecting groups. The P-lactam has the following structural formula (3):

X

5 ' 0 Nf X OP 2 (3) wherein P 2 is a hydroxy protecting group and X 3 and X 5 are as previously defined and the alkoxide has the structural formula (4): P100 0 -- R7 HO -. BzOAcO 20 (4) wherein M is a metal or ammonium, P,, is a hydroxy protecting group and R 7 is as previously defined. The alkoxide may be prepared from 10-deacetylbaccatin IlIl by selective protection of the C-10 hydroxyl group and then esterification of the C-7 hydroxyl WO 01/57029 PCT/USO1/03600 7 group (as described more fully in Holton et al., PCT Patent Application WO 99/09021) followed by treatment with a metallic amide. Derivatives of 10-deacetylbaccatin Ill having alternative substituents at C(2), C(9) and C(14) and processes for their preparation are known in the art. 5 Taxane derivatives having acyloxy substituents other than benzoyloxy at C(2) may be prepared, for example, as described in Holton et al., U.S. Patent No. 5,728,725 or Kingston et al., U.S. Patent No. 6,002,023. Taxanes having acyloxy or hydroxy substituents at C(9) in place of keto may be prepared, for example as described in Holton et al., U.S. Patent No. 6,011,056 or Gunawardana et al., U.S. 10 Patent No. 5,352,806. Taxanes having a beta hydroxy substituent at C(14) may be prepared from naturally occurring 14-hydroxy-10-deacetylbaccatin llI. Processes for the preparation and resolution of the p-lactam starting material are generally well known. For example, the P-lactam may be prepared as described in Holton, U.S. Patent No. 5,430,160 and the resulting enatiomeric 15 mixtures of P-lactams may be resolved by a stereoselective hydrolysis using a lipase or enzyme as described, for example, in Patel, U.S. Patent No. 5,879,929 Patel U.S. Patent No. 5,567,614 or a liver homogenate as described, for example, in PCT Patent Application No. 00/41204. In a preferred embodiment in which the P-lactam is furyl substituted at the C(4) position, the p-lactam can be prepared as 20 illustrated in the following reaction scheme: WO 01/57029 PCT/USO1/03600 8

NH

2 Step A C toluene N OCH3 + AcO Cl 0 CO0Q ZOCI- 3 0

OCH

3 5 6 7 8 Step B H 3 CO Step C H 3 CO Step D tolen 0 0 AIC toluene NfO Beef Liver N CAN, CH 3 CN NEt 3 OAc Resolution V "OAc (t) 9 (+) 9 Step E Step F HN O KOH HN O p-TsOH HN O OkOH OMe OMe (-) 10 (+ 1(-) 12 wherein Ac is acetyl, NEt 3 is triethylamine, CAN is ceric ammonium nitrate, and p TsOH is p-toluenesulfonic acid. The beef liver resolution may be carried out, for example, by combining the enatiomeric P-lactam mixture with a beef liver suspension (prepared, for example, by adding 20 g of frozen beef liver to a 5 blender and then adding a pH 8 buffer to make a total volume of 1 L). Compounds of formula 1 of the instant invention are useful for inhibiting tumor growth in mammals including humans and are preferably administered in the form of a pharmaceutical composition comprising an effective antitumor amount of a compound of the instant invention in combination with at least one 10 pharmaceutically or pharmacologically acceptable carrier. The carrier, also known in the art as an excipient, vehicle, auxiliary, adjuvant, or diluent, is any substance which is pharmaceutically inert, confers a suitable consistency or form to the composition, and does not diminish the therapeutic efficacy of the antitumor compounds. The carrier is "pharmaceutically or pharmacologically acceptable" if WO 01/57029 PCT/USO1/03600 9 it does not produce an adverse, allergic or other untoward reaction when administered to a mammal or human, as appropriate. The pharmaceutical compositions containing the antitumor compounds of the present invention may be formulated in any conventional manner. Proper 5 formulation is dependent upon the route of administration chosen. The compositions of the invention can be formulated for any route of administration so long as the target tissue is available via that route. Suitable routes of administration include, but are not limited to, oral, parenteral (e.g., intravenous, intraarterial, subcutaneous, rectal, subcutaneous, intramuscular, intraorbital, 10 intracapsular, intraspinal, intraperitoneal, or intrasternal), topical (nasal, transdermal, intraocular), intravesical, intrathecal, enteral, pulmonary, intralymphatic, intracavital, vaginal, transurethral, intradermal, aural, intramammary, buccal, orthotopic, intratracheal, intralesional, percutaneous, endoscopical, transmucosal, sublingual and intestinal administration. 15 Pharmaceutically acceptable carriers for use in the compositions of the present invention are well known to those of ordinary skill in the art and are selected based upon a number of factors: the particular antitumor compound used, and its concentration, stability and intended bioavailability; the disease, disorder or condition being treated with the composition; the subject, its age, size 20 and general condition; and the route of administration. Suitable carriers are readily determined by one of ordinary skill in the art (see, for example, J. G. Nairn, in: Remington's Pharmaceutical Science (A. Gennaro, ed.), Mack Publishing Co., Easton, Pa., (1985), pp. 1492-1517, the contents of which are incorporated herein by reference). 25 The compositions are preferably formulated as tablets, dispersible powders, pills, capsules, gelcaps, caplets, gels, liposomes, granules, solutions, suspensions, emulsions, syrups, elixirs, troches, dragees, lozenges, or any other dosage form which can be administered orally. Techniques and compositions for making oral dosage forms useful in the present invention are described in the 30 following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Lieberman et al., Pharmaceutical Dosaqe Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976). The compositions of the invention for oral administration comprise an 35 effective antitumor amount of a compound of the invention in a pharmaceutically acceptable carrier. Suitable carriers for solid dosage forms include sugars, WO 01/57029 PCT/USO1/03600 10 starches, and other conventional substances including lactose, talc, sucrose, gelatin, carboxymethylcellulose, agar, mannitol, sorbitol, calcium phosphate, calcium carbonate, sodium carbonate, kaolin, alginic acid, acacia, corn starch, potato starch, sodium saccharin, magnesium carbonate, tragacanth, 5 microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, and stearic acid. Further, such solid dosage forms may be uncoated or may be coated by known techniques; e.g., to delay disintegration and absorption. The antitumor compounds of the present invention are also preferably 10 formulated for parenteral administration, e.g., formulated for injection via intravenous, intraarterial, subcutaneous, rectal, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal, or intrasternal routes. The compositions of the invention for parenteral administration comprise an effective antitumor amount of the antitumor compound in a pharmaceutically acceptable 15 carrier. Dosage forms suitable for parenteral administration include solutions, suspensions, dispersions, emulsions or any other dosage form which can be administered parenterally. Techniques and compositions for making parenteral dosage forms are known in the art. Suitable carriers used in formulating liquid dosage forms for oral or 20 parenteral administration include nonaqueous, pharmaceutically-acceptable polar solvents such as oils, alcohols, amides, esters, ethers, ketones, hydrocarbons and mixtures thereof, as well as water, saline solutions, dextrose solutions (e.g., DW5), electrolyte solutions, or any other aqueous, pharmaceutically acceptable liquid. 25 Suitable nonaqueous, pharmaceutically-acceptable polar solvents include, but are not limited to, alcohols (e.g., a-glycerol formal, p-glycerol formal, 1, 3 butylerieglycol, aliphatic or aromatic alcohols having 2-30 carbon atoms such as methanol, ethanol, propanol, isopropanol, butanol, t-butanol, hexanol, octanol, amylene hydrate, benzyl alcohol, glycerin (glycerol), glycol, hexylene glycol, 30 tetrahydrofurfuryl alcohol, lauryl alcohol, cetyl alcohol, or stearyl alcohol, fatty acid esters of fatty alcohols such as polyalkylene glycols (e.g., polypropylene glycol, polyethylene glycol), sorbitan, sucrose and cholesterol); amides (e.g., dimethylacetamide (DMA), benzyl benzoate DMA, dimethylformamide, N-(P hydroxyethyl)-lactamide, N, N-dimethylacetamide-amides, 2-pyrrolidinone, 35 1-methyl-2-pyrrolidinone, or polyvinylpyrrolidone); esters (e.g., 1-methyl-2 pyrrolidinone, 2-pyrrolidinone, acetate esters such as monoacetin, diacetin, and WO 01/57029 PCT/USO1/03600 11 triacetin, aliphatic or aromatic esters such as ethyl caprylate or octanoate, alkyl oleate, benzyl benzoate, benzyl acetate, dimethylsulfoxide (DMSO), esters of glycerin such as mono, di, or tri-glyceryl citrates or tartrates, ethyl benzoate, ethyl acetate, ethyl carbonate, ethyl lactate, ethyl oleate, fatty acid esters of sorbitan, 5 fatty acid derived PEG esters, glyceryl monostearate, glyceride esters such as mono, di, or tri-glycerides, fatty acid esters such as isopropyl myristrate, fatty acid derived PEG esters such as PEG-hydroxyoleate and PEG-hydroxystearate, N methyl pyrrolidinone, pluronic 60, polyoxyethylene sorbitol oleic polyesters such as poly(ethoxylated) 30

.

60 sorbitol poly(oleate) 2

.

4 . poly(oxyethylene) 1

..

2 0 monooleate, 10 poly(oxyethylene) 1 5

-

2 0 mono 12-hydroxystearate, and poly(oxyethylene) 1 5

-

2 0 mono ricinoleate, polyoxyethylene sorbitan esters such as polyoxyethylene-sorbitan monooleate, polyoxyethylene-sorbitan monopalmitate, polyoxyethylene-sorbitan monolaurate, polyoxyethylene-sorbitan monostearate, and Polysorbate@ 20, 40, 60 or 80 from ICI Americas, Wilmington, DE, polyvinylpyrrolidone, alkyleneoxy 15 modified fatty acid esters such as polyoxyl 40 hydrogenated castor oil and polyoxyethylated castor oils (e.g., Cremophor@ EL solution or Cremophor@ RH 40 solution), saccharide fatty acid esters (i.e., the condensation product of a monosaccharide (e.g., pentoses such as ribose, ribulose, arabinose, xylose, lyxose and xylulose, hexoses such as glucose, fructose, galactose, mannose and 20 sorbose, trioses, tetroses, heptoses, and octoses), disaccharide (e.g., sucrose, maltose, lactose and trehalose) or oligosaccharide or mixture thereof with a C4_ C22 fatty acid(s)(e.g., saturated fatty acids such as caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid and stearic acid, and unsaturated fatty acids such as palmitoleic acid, oleic acid, elaidic acid, erucic acid and linoleic acid)), or 25 steroidal esters); alkyl, aryl, or cyclic ethers having 2-30 carbon atoms (e.g., diethyl ether, tetrahydrofuran, dimethyl isosorbide, diethylene glycol monoethyl ether); glycofurol (tetrahydrofurfuryl alcohol polyethylene glycol ether); ketones having 3-30 carbon atoms (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone); aliphatic, cycloaliphatic or aromatic hydrocarbons having 4-30 carbon 30 atoms (e.g., benzene, cyclohexane, dichloromethane, dioxolanes, hexane, n decane, n-dodecane, n-hexane, sulfolane, tetramethylenesulfon, tetramethylenesulfoxide, toluene, dimethylsulfoxide (DMSO), or tetramethylenesulfoxide); oils of mineral, vegetable, animal, essential or synthetic origin (e.g., mineral oils such as aliphatic or wax-based hydrocarbons, aromatic 35 hydrocarbons, mixed aliphatic and aromatic based hydrocarbons, and refined paraffin oil, vegetable oils such as linseed, tung, safflower, soybean, castor, WO 01/57029 PCT/USO1/03600 12 cottonseed, groundnut, rapeseed, coconut, palm, olive, corn, corn germ, sesame, persic and peanut oil and glycerides such as mono-, di- or triglycerides, animal oils such as fish, marine, sperm, cod-liver, haliver, squalene, squalane, and shark liver oil, oleic oils, and polyoxyethylated castor oil); alkyl or aryl halides having 1 5 30 carbon atoms and optionally more than one halogen substituent; methylene chloride; monoethanolamine; petroleum benzin; trolamine; omega-3 polyunsaturated fatty acids (e.g., alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid, or docosahexaenoic acid); polyglycol ester of 12-hydroxystearic acid and polyethylene glycol (Solutol@ HS-1 5, from BASF, 10 Ludwigshafen, Germany); polyoxyethylene glycerol; sodium laurate; sodium oleate; or sorbitan monooleate. Other pharmaceutically acceptable solvents for use in the invention are well known to those of ordinary skill in the art, and are identified in The Chemotherapy Source Book (Williams & Wilkens Publishing), The Handbook of 15 Pharmaceutical Excipients, (American Pharmaceutical Association, Washington, D.C., and The Pharmaceutical Society of Great Britain, London, England, 1968), Modern Pharmaceutics, (G. Banker et al., eds., 3d ed.)(Marcel Dekker, Inc., New York, New York, 1995), The Pharmacological Basis of Therapeutics, (Goodman & Gilman, McGraw Hill Publishing), Pharmaceutical Dosage Forms, (H. Lieberman 20 et al., eds., )(Marcel Dekker, Inc., New York, New York, 1980), Remington's Pharmaceutical Sciences (A. Gennaro, ed., 19th ed.)(Mack Publishing, Easton, PA, 1995), The United States Pharmacopeia 24, The National Formulary 19, (National Publishing, Philadelphia, PA, 2000), A.J. Spiegel et al., and Use of Nonaqueous Solvents in Parenteral Products, JOURNAL OF PHARMACEUTICAL 25 SCIENCES, Vol. 52, No. 10, pp. 917-927 (1963). Preferred solvents include those known to stabilize the antitumor compounds, such as oils rich in triglycerides, for example, safflower oil, soybean oil or mixtures thereof, and alkyleneoxy modified fatty acid esters such as polyoxyl 40 hydrogenated castor oil and polyoxyethylated castor oils (e.g., 30 Cremophor@ EL solution or Cremophor@ RH 40 solution). Commercially available triglycerides include Intralipid@ emulsified soybean oil (Kabi-Pharmacia Inc., Stockholm, Sweden), Nutralipid @ emulsion (McGaw, Irvine, California), Liposyn® 1I 20% emulsion (a 20% fat emulsion solution containing 100 mg safflower oil, 100 mg soybean oil, 12 mg egg phosphatides, and 25 mg glycerin 35 per ml of solution; Abbott Laboratories, Chicago, Illinois), Liposyn@ III 2% emulsion (a 2% fat emulsion solution containing 100 mg safflower oil, 100 mg WO 01/57029 PCT/USO1/03600 13 soybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml of solution; Abbott Laboratories, Chicago, Illinois), natural or synthetic glycerol derivatives containing the docosahexaenoy group at levels between 25% and 100% by weight based on the total fatty acid content (Dhasco@ (from Martek Biosciences 5 Corp., Columbia, MD), DHA Maguro@ (from Daito Enterprises, Los Angeles, CA), Soyacal@, and Travemulsion@. Ethanol is a preferred solvent for use in dissolving the antitumor compound to form solutions, emulsions, and the like. Additional minor components can be included in the compositions of the invention for a variety of purposes well known in the pharmaceutical industry. 10 These components will for the most part impart properties which enhance retention of the antitumor compound at the site of administration, protect the stability of the composition, control the pH, facilitate processing of the antitumor compound into pharmaceutical formulations, and the like. Preferably, each of these components is individually present in less than about 15 weight % of the 15 total composition, more preferably less than about 5 weight %, and most preferably less than about 0.5 weight % of the total composition. Some components, such as fillers or diluents, can constitute up to 90 wt.% of the total composition, as is well known in the formulation art. Such additives include cryoprotective agents for preventing reprecipitation of the taxane, surface active, 20 wetting or emulsifying agents (e.g., lecithin, polysorbate-80, Tween@ 80, pluronic 60, polyoxyethylene stearate ), preservatives (e.g., ethyl-p-hydroxybenzoate), microbial preservatives (e.g., benzyl alcohol, phenol, m-cresol, chlorobutanol, sorbic acid, thimerosal and paraben), agents for adjusting pH or buffering agents (e.g., acids, bases, sodium acetate, sorbitan monolaurate), agents for adjusting 25 osmolarity (e.g., glycerin), thickeners (e.g., aluminum monostearate, stearic acid, cetyl alcohol, stearyl alcohol, guar gum, methyl cellulose, hydroxypropylcellulose, tristearin, cetyl wax esters, polyethylene glycol), colorants, dyes, flow aids, non-volatile silicones (e.g., cyclomethicone), clays (e.g., bentonites), adhesives, bulking agents, flavorings, sweeteners, adsorbents, fillers (e.g., sugars such as 30 lactose, sucrose, mannitol, or sorbitol, cellulose, or calcium phosphate), diluents (e.g., water, saline, electrolyte solutions), binders (e.g., starches such as maize starch, wheat starch, rice starch, or potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, sugars, polymers, acacia), disintegrating agents (e.g., 35 starches such as maize starch, wheat starch, rice starch, potato starch, or carboxymethyl starch, cross-linked polyvinyl pyrrolidone, agar, alginic acid or a WO 01/57029 PCT/USO1/03600 14 salt thereof such as sodium alginate, croscarmellose sodium or crospovidone), lubricants (e.g., silica, talc, stearic acid or salts thereof such as magnesium stearate, or polyethylene glycol), coating agents (e.g., concentrated sugar solutions including gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, 5 polyethylene glycol, or titanium dioxide), and antioxidants (e.g., sodium metabisulfite, sodium bisulfite, sodium sulfite, dextrose, phenols, and thiophenols). In a preferred embodiment, a pharmaceutical composition of the invention comprises at least one nonaqueous, pharmaceutically acceptable solvent and an 10 antitumor compound having a solubility in ethanol of at least about 100, 200, 300, 400, 500, 600, 700 or 800 mg/ml. While not being bound to a particular theory, it is believed that the ethanol solubility of the antitumor compound may be directly related to its efficacy. The antitumor compound can also be capable of being crystallized from a solution. In other words, a crystalline antitumor compound, 15 such as compound 1393, can be dissolved in a solvent to form a solution and then recrystallized upon evaporation of the solvent without the formation of any amorphous antitumor compound. It is also preferred that the antitumor compound have an ID50 value (i.e, the drug concentration producing 50% inhibition of colony formation) of at least 4, 5, 6, 7, 8, 9, or 10 times less that of paclitaxel 20 when measured according to the protocol set forth in the working examples. Dosage form administration by these routes may be continuous or intermittent, depending, for example, upon the patient's physiological condition, whether the purpose of the administration is therapeutic or prophylactic, and other factors known to and assessable by a skilled practitioner. 25 Dosage and regimens for the administration of the pharmaceutical compositions of the invention can be readily determined by those with ordinary skill in treating cancer. It is understood that the dosage of the antitumor compounds will be dependent upon the age, sex, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the 30 nature of the effect desired. For any mode of administration, the actual amount of antitumor compound delivered, as well as the dosing schedule necessary to achieve the advantageous effects described herein, will also depend, in part, on such factors as the bioavailability of the antitumor compound, the disorder being treated, the desired therapeutic dose, and other factors that will be apparent to 35 those of skill in the art. The dose administered to an animal, particularly a human, in the context of the present invention should be sufficient to effect the desired WO 01/57029 PCT/US01/03600 15 therapeutic response in the animal over a reasonable period of time. Preferably, an effective amount of the antitumor compound, whether administered orally or by another route, is any amount which would result in a desired therapeutic response when administered by that route. Preferably, the compositions for oral 5 administration are prepared in such a way that a single dose in one or more oral preparations contains at least 20 mg of the antitumor compound per m 2 Of patient body surface area, orat least 50, 100, 150, 200, 300, 400, or 500 mg of the antitumor compound per m 2 of patient body surface area, wherein the average body surface area for a human is 1.8 M 2 . Preferably, a single dose of a 10 composition for oral administration contains from about 20 to about 600 mg of the antitumor compound per M 2 of patient body surface area, more preferably from about 25 to about 400 mg/m 2 , even more preferably, from about 40 to about 300 mg/m 2 , and even more preferably from about 50 to about 200 mg/m 2 . Preferably, the compositions for parenteral administration are prepared in such a way that a 15 single dose contains at least 20 mg of the antitumor compound per m 2 of patient body surface area, or at least 40, 50, 100, 150, 200, 300, 400, or 500 mg of the antitumor compound per m 2 of patient body surface area. Preferably, a single dose in one or more parenteral preparations contains from about 20 to about 500 mg of the antitumor compound per m 2 Of patient body surface area, more 20 preferably from about 40 to about 400 mg/m 2 , and even more preferably, from about 60 to about 350 mg/m 2 . However, the dosage may vary depending on the dosing schedule which can be adjusted as necessary to achieve the desired therapeutic effect. It should be noted that the ranges of effective doses provided herein are not intended to limit the invention and represent preferred dose 25 ranges. The most preferred dosage will be tailored to the individual subject, as is understood and determinable by one of ordinary skill in the art without undue experimentation. The concentration of the antitumor compound in a liquid pharmaceutical composition is preferably between about 0.01 mg and about 10 mg per ml of the 30 composition, more preferably between about 0.1 mg and about 7 mg per ml, even more preferably between about 0.5 mg and about 5 mg per ml, and most preferably between about 1.5 mg and about 4 mg per ml. Relatively low concentrations are generally preferred because the antitumor compound is most soluble in the solution at low concentrations. The concentration of the antitumor 35 compound in a solid pharmaceutical composition for oral administration is preferably between about 5 weight % and about 50 weight %, based on the total WO 01/57029 PCT/USO1/03600 16 weight of the composition, more preferably between about 8 weight % and about 40 weight %, and most preferably between about 10 weight % and about 30 weight %. In one embodiment, solutions for oral administration are prepared by 5 dissolving an antitumor compound in any pharmaceutically acceptable solvent capable of dissolving the compound (e.g., ethanol or methylene chloride) to form a solution. An appropriate volume of a carrier which is a solution, such as Cremophor@ EL solution, is added to the solution while stirring to form a pharmaceutically acceptable solution for oral administration to a patient. If 10 desired, such solutions can be formulated to contain a minimal amount of, or to be free of, ethanol, which is known in the art to cause adverse physiological effects when administered at certain concentrations in oral formulations. In another embodiment, powders or tablets for oral administration are prepared by dissolving an antitumor compound in any pharmaceutically 15 acceptable solvent capable of dissolving the compound (e.g.,ethanol or methylene chloride) to form a solution. The solvent can optionally be capable of evaporating when the solution is dried under vacuum. An additional carrier can be added to the solution prior to drying, such as Cremophor@ EL solution. The resulting solution is dried under vacuum to form a glass. The glass is then mixed 20 with a binder to form a powder. The powder can be mixed with fillers or other conventional tabletting agents and processed to form a tablet for oral administration to a patient. The powder can also be added to any liquid carrier as described above to form a solution, emulsion, suspension or the like for oral administration. 25 Emulsions for parenteral administration can be prepared by dissolving an antitumor compound in any pharmaceutically acceptable solvent capable of dissolving the compound (e.g., ethanol or methylene chloride) to form a solution. An appropriate volume of a carrier which is an emulsion, such as Liposyn@ ll or Liposyn@ IlIl emulsion, is added to the solution while stirring to form a 30 pharmaceutically acceptable emulsion for parenteral administration to a patient. If desired, such emulsions can be formulated to contain a minimal amount of, or to be free of, ethanol or Cremophor@ solution, which are known in the art to cause adverse physiological effects when administered at certain concentrations in parenteral formulations. 35 Solutions for parenteral administration can be prepared by dissolving an antitumor compound in any pharmaceutically acceptable solvent capable of WO 01/57029 PCT/USO1/03600 17 dissolving the compound (e.g., ethanol or methylene chloride) to form a solution. An appropriate volume of a carrier which is a solution, such as Cremophor@ solution, is added to the solution while stirring to form a pharmaceutically acceptable solution for parenteral administration to a patient. If desired, such 5 solutions can be formulated to contain a minimal amount of, or to be free of, ethanol or Cremophor@ solution, which are known in the art to cause adverse physiological effects when administered at certain concentrations in parenteral formulations. If desired, the emulsions or solutions described above for oral or parenteral 10 administration can be packaged in IV bags, vials or other conventional containers in concentrated form and diluted with any pharmaceutically acceptable liquid, such as saline, to form an acceptable taxane concentration prior to use as is known in the art. Definitions 15 The terms "hydrocarbon" and "hydrocarbyl" as used herein describe organic compounds or radicals consisting exclusively of the elements carbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, and aryl moieties. These moieties also include alkyl, alkenyl, alkynyl, and aryl moieties substituted with other aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl and 20 alkynaryl. Unless otherwise indicated, these moieties preferably comprise 1 to 20 carbon atoms. The "substituted hydrocarbyl" moieties described herein are hydrocarbyl moieties which are substituted with at least one atom other than carbon, including moieties in which a carbon chain atom is substituted with a hetero atom such as 25 nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or a halogen atom. These substituents include halogen, heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyl, acyloxy, nitro, amino, amido, nitro, cyano, thiol, ketals, acetals, esters and ethers. The term "heteroatom" shall mean atoms other than carbon and hydrogen. 30 The "heterosubstituted methyl" moieties described herein are methyl groups in which the carbon atom is covalently bonded to at least one heteroatom and optionally with hydrogen, the heteroatom being, for example, a nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or halogen atom. The heteroatom may, in turn, be substituted with other atoms to form a heterocyclo, alkoxy, WO 01/57029 PCT/USO1/03600 18 alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, oxy, acyloxy, nitro, amino, amido, thiol, ketals, acetals, esters or ether moiety. The "heterosubstituted acetate" moieties described herein are acetate groups in which the carbon of the methyl group is covalently bonded to at least 5 one heteroatom and optionally with hydrogen, the heteroatom being, for example, a nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or halogen atom. The heteroatom may, in turn, be substituted with other atoms to form a heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, oxy, acyloxy, nitro, amino, amido, thiol, ketals, acetals, esters or ether moiety. 10 Unless otherwise indicated, the alkyl groups described herein are preferably lower alkyl containing from one to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include methyl, ethyl, propyl, isopropyl, butyl, hexyl and the like. Unless otherwise indicated, the alkenyl groups described herein are 15 preferably lower alkenyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like. Unless otherwise indicated, the alkynyl groups described herein are 20 preferably lower alkynyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain and include ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like. The terms "aryl" or "ar" as used herein alone or as part of another group denote optionally substituted homocyclic aromatic groups, preferably monocyclic 25 or bicyclic groups containing from 6 to 12 carbons in the ring portion, such as phenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyl or substituted naphthyl. Phenyl and substituted phenyl are the more preferred aryl. The terms "halogen" or "halo" as used herein alone or as part of another group refer to chlorine, bromine, fluorine, and iodine. 30 The terms "heterocyclo" or "heterocyclic" as used herein alone or as part of another group denote optionally substituted, fully saturated or unsaturated, monocyclic or bicyclic, aromatic or nonaromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring. The heterocyclo group preferably has 1 or 2 oxygen atoms, 1 or 2 sulfur atoms, and/or 35 1 to 4 nitrogen atoms in the ring, and may be bonded to the remainder of the molecule through a carbon or heteroatom. Exemplary heterocyclo include WO 01/57029 PCT/USO1/03600 19 heteroaromatics such as furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, or isoquinolinyl and the like. Exemplary substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, keto, hydroxy, protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, 5 amino, nitro, cyano, thiol, ketals, acetals, esters and ethers. The term "heteroaromatic" as used herein alone or as part of another group denote optionally substituted aromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring. The heteroaromatic group preferably has I or 2 oxygen atoms, 1 or 2 sulfur atoms, 10 and/or 1 to 4 nitrogen atoms in the ring, and may be bonded to the remainder of the molecule through a carbon or heteroatom. Exemplary heteroaromatics include furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, or isoquinolinyl and the like. Exemplary substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, keto, hydroxy, protected hydroxy, acyl, 15 acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers. The term "acyl," as used herein alone or as part of another group, denotes the moiety formed by removal of the hydroxyl group from the group --COOH of an organic carboxylic acid, e.g., RC(O)-, wherein R is R 1 , R 1 0-, R 1

R

2 N-, or R'S-, R' is 20 hydrocarbyl, heterosubstituted hydrocarbyl, or heterocyclo and R 2 is hydrogen, hydrocarbyl or substituted hydrocarbyl. The term "acyloxy," as used herein alone or as part of another group, denotes an acyl group as described above bonded through an oxygen linkage (--0--), e.g., RC(0)0- wherein R is as defined in connection with the term "acyl." 25 Unless otherwise indicated, the alkoxycarbonyloxy moieties described herein comprise lower hydrocarbon or substituted hydrocarbon or substituted hydrocarbon moieties. Unless otherwise indicated, the carbamoyloxy moieties described herein are derivatives of carbamic acid in which one or both of the amine hydrogens is 30 optionally replaced by a hydrocarbyl, substituted hydrocarbyl or heterocyclo moiety. The terms "hydroxyl protecting group" and "hydroxy protecting group" as used herein denote a group capable of protecting a free hydroxyl group ("protected hydroxyl") which, subsequent to the reaction for which protection is 35 employed, may be removed without disturbing the remainder of the molecule. A variety of protecting groups for the hydroxyl group and the synthesis thereof may WO 01/57029 PCT/USO1/03600 20 be found in "Protective Groups in Organic Synthesis" by T. W. Greene, John Wiley and Sons, 1981, or Fieser & Fieser. Exemplary hydroxyl protecting groups include methoxymethyl, I-ethoxyethyl, benzyloxymethyl, (.beta.-trimethylsilylethoxy)methyl, tetrahyd ropyranyl, 5 2,2,2-trichloroethoxycarbonyl, t-butyl(diphenyl)silyl, trialkylsilyl, trichloromethoxycarbonyl and 2,2,2-trichloroethoxymethyl. As used herein, "Ac" means acetyl; "Bz" means benzoyl; "Et" means ethyl; "Me" means methyl; "Ph" means phenyl; "iPr" means isopropyl; "tBu" and "t-Bu" means tert-butyl; "R" means lower alkyl unless otherwise defined; "py" means 10 pyridine or pyridyl; "TES" means triethylsilyl; "TMS" means trimethylsilyl; "LAH" means lithium aluminum hydride; "10-DAB" means 10-desacetylbaccatin Ill"; "amine protecting group" includes, but is not limited to, carbamates, for example, 2,2,2-trichloroethylcarbamate or tertbutylcarbamate; "protected hydroxy" means OP wherein P is a hydroxy protecting group; "PhCO" means phenylcarbonyl; 15 "tBuOCO" and "Boc" mean tert-butoxycarbonyl; "tAmOCO" means tert amyloxycarbonyl; "2-FuCO" means 2-furylcarbonyl; "2-ThCO" means 2 thienylcarbonyl; "3-ThCO" means 3-thienylcarbonyl; "2-PyCO" means 2 pyridylcarbonyl; "3-PyCO" means 3-pyridylcarbonyl; "4-PyCO" means 4 pyridylcarbonyl; "C 4

H

7 CO" means butenylcarbonyl; "tC 3 HCO" means trans 20 propenylcarbonyl; "EtOCO" means ethoxycarbonyl; "ibueCO" means isobutenylcarbonyl; "iBuCO" means isobutylcarbonyl; "iBuOCO" means isobutoxycarbonyl; "iPrOCO" means isopropyloxycarbonyl; "nPrOCO" means n propyloxycarbonyl; "nPrCO" means n-propylcarbonyl,"ibue" means isobutenyl; "THF" means tetrahydrofuran; "DMAP" means 4-dimethylamino pyridine; and 25 "LHMDS" means lithium hexamethyl disilazanide. The following examples illustrate the invention. Example 1 N-Debenzoyl-N-tert-amyloxycarbonyl-3'-desphenyl-3'-(2-furyl) 10-deacetyl-7-methoxyacetyl taxol (6226) 30 To a solution of N-debenzoy-N-tert-amyloxycarbonyl-3'-desphenyl-3'-(2-furyl)-2'-(2 methoxy-2-propyl)-7-benzyloxycarbonyl-1 0-deacetyl-1 0-trimethylsilyl taxol (2.50 g, 2.292 mmol) in 50 mL of ethyl acetate was added 10% Pd-C (500 mg) and the mixture stirred at ambient temperature under a H 2 atmosphere (latex balloons) for WO 01/57029 PCT/USO1/03600 21 45 minutes. TLC of the reaction (silica gel, 1:1 ethyl acetate:hexane) showed the presence of only the product. The mixture was then filtered through a celite bed (5 g) and the celite washed with 25 mL of ethyl acetate. The combined ethyl acetate fraction was concentrated under reduced pressure to give, the N-debenzoy-N-tert 5 amyloxycarbonyl-3'-desphenyl-3'-(2-furyl)-2'-(2-methoxy-2-propyl)-1 0-deacetyl-1 0 trimethylsilyl taxol as a white solid 2.10 g (96%) which was directly used in the next step. To a solution of N-debenzoyl-N-tert-amyloxycarbonyl-3'-desphenyl-3'-(2-furyl)-2'-(2 methoxy-2-propyl)-10-deacetyl-10-trimethylsilyl taxol (400 mg, 0.418 mmol) in 4 mL 10 anhydrous pyridine at 0 OC was added DMAP (20 mg, 0.16 mmol) under a nitrogen atmosphere. To this mixture was added drop wise methoxyacety chloride (96 mL, 1.045 mmol). TLC (silica gel, 2:3 ethyl acetate:hexane) after 3 h showed no starting material. The reaction was cooled to 0 0C (ice-water bath) and quenched by adding 80 mL of water. 15 To the reaction at 0 0C (ice-water bath) was added 4 mL of acetonitrile and 2 mL of 48% aqueous hydrofluoric acid and the cooling bath was removed. The reaction was stirred at room temperature for 8.0 h and then diluted with 60 mL of ethyl acetate and washed with 2x1 0 mL of saturated aqueous NaHCO 3 followed by 15 mL of saturated aqueous NaCl. The organic layer was dried over Na 2

SO

4 and concentrated under 20 reduced pressure to give 365 mg of a yellow solid which was purified by flash chromatography (silica gel, 1:1 ethyl acetate:hexane) to give 325 mg (88%) of N debenzoyl-N-tert-amyloxycarbonyl-3'-desphenyl-3'-(2-furyl)-1 0-deacetyl-7 methoxyacetyl taxol: mp 166-167 0C; 'H NMR (CDC 3 ) 8.12 (m, 2H), 7.62(m, 1H), 7.46-7.51(m, 2H), 7.40 (m, 1H), 6.39(dd, J=3.1, 1.5 Hz, 1H), 6.25 (d, J=3.1 Hz, IH), 25 6.21 (dd, J=8.8, 8.7 Hz, 1 H), 5.67(1 H), 5.58 (m, I H), 5.26-5.38(m, 3H), 4.98(m, 1 H), 4.76(m, IH), 4.36 (d, J=9.3 Hz, 1H), 4.21 (d, J=9.3 Hz, IH), 4.09(d, J=7.6 Hz, IH), 3.99 (m, 3H), 3.42 (s, 3H), 3.30 (d, J= 5.5 Hz, IH), 2.55-2.60(m, IH), 2.43 (s, 3H), 2.20-2.38(m,2H), 1.98 (s, 3H), 1.96-1.98 (m, 1 H), 1.84 (bs, 3H), 1.62-1.68(m, 2H), 1.36(s, 3H), 1.34(s, 3H), 1.23(s, 3H), 1.10(s, 3H), 0.81(t, J=8.2Hz, 3H); Anal. Calcd. 30 for C 45

H

57

NO

17 : C, 61.15; H, 6.50. Found: C, 61.01; H, 6.57.

WO 01/57029 PCT/USO1/03600 22 Example 2 The procedures described in Example I were repeated, but other suitably protected P-lactams were substituted for the P-lactam of Example 1 to prepare the series of compounds having structural formula (13) and the combinations of 5 substituents identified in the following table HO

X

5 NH O 0 X3 0 l .. R7 OH HO. BzkO z Aco O (13) Compound X 5 X3 R7 5544 ibueCO- 2-furyl AcOAcO 5474 ibueCO- 2-furyl MeOAcO 10 5555 ibueCO- 2-furyl PhOAcO 5999 ibueCO- 2-furyl MeOAcO 6353 tAmOCO- 2-furyl AcOAcO 6226 tAmOCO- 2-furyl MeOAcO 5622 tBuOCO- 2-furyl AcOAcO 15 5515 tBuOCO- 2-furyl EtOAcO 5445 tBuOCO- 2-furyl MeOAcO 5600 tBuOCO- 2-furyl MeSAcO 5616 tBuOCO- 2-furyl PhOAcO 5835 tC 3

H

5 CO- 2-furyl MeOAcO 20 5811 tC 3

H

5 CO- 2-furyl PhOAcO 5919 C 3 HCO- 2-furyl PhOAcO 6326 tBuOCO- 2-furyl MeOAcO- WO 01/57029 PCT/USO1/03600 23 Example 3 Following the processes described elsewhere herein, the following specific taxanes having structural formula I may be prepared, wherein R 7 is as previously defined, including wherein R 7 is R 7 aCOO- and R 7 a is heterosubstituted methyl. In one 5 embodiment, R 7 a is chloromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, phenoxymethyl, acetoxymethyl, or methylthiomethyl.

X

5 NH O HO X3 OOH - R7 HO BzOAOO X5 X3 R7 tBuOCO- 2-furyl

R

7 aCOO tBuOCO- 3-furyl

R

7 aCOO 10 tBuOCO- 2-thienyl

R

7 aCOO tBuOCO- 3-thienyl

R

7 aCOO tBuOCO- 2-pyridyl

R

7 aCOO tBuOCO- 3-pyridyl

R

7 aCOO tBuOCO- 4-pyridyl

R

7 aCOO 15 tBuOCO- isobutenyl R 7 aCOO tBuOCO- isopropyl

R

7 aCOO tBuOCO- cyclopropyl

R

7 aCOO tBuOCO- cyclobutyl

R

7 aCOO tBuOCO- cyclopentyl R 7 aCOO 20 tBuOCO- phenyl

R

7 aCOO benzoyl 2-furyl

R

7 aCOO benzoyl 3-furyl

R

7 aCOO benzoyl 2-thienyl

R

7 aCOO benzoyl 3-thienyl

R

7 aCOO 2b t enzoyl 2-pyridyl RyaCOO- WO 01/57029 PCT/USO1/03600 24 benzoyl 3-pyridyl

R

7 aCOO benzoyl 4-pyridyl

R

7 1COO benzoyl isobutenyl

R

7 aCOO benzoyl isopropyl

R

7 aCOO 5 benzoyl cyclopropyl

R

7 aCOO benzoyl cyclobutyl

R

7 aCOO benzoyl cyclopentyl

R

7 zCOO benzoyl phenyl

R

7 aCOO 2-FuCO- 2-furyl

R

7 aCOO 10 2-FuCO- 3-furyl

R

7 aCOO 2-FuCO- 2-thienyl R 7 aCOO 2-FuCO- 3-thienyl

R

7 aCOO 2-FuCO- 2-pyridyl

R

7 aCOO 2-FuCO- 3-pyridyl

R

7 aCOO 15 2-FuCO- 4-pyridyl

R

7 aCOO 2-FuCO- isobutenyl R 7

,COO

2-FuCO- isopropyl

R

7 aCOO 2-FuCO- cyclopropyl R 7

,COO

2-FuCO- cyclobutyl

R

7 aCOO 20 2-FuCO- cyclopentyl

R

7 aCOO 2-FuCO- phenyl

R

7 aCOO 2-ThCO- 2-furyl

R

7 aCOO 2-ThCO- 3-furyl

R

7 aCOO 2-ThCO- 2-thienyl

R

7 aCOO 25 2-ThCO- 3-thienyl

R

7 aCOO 2-ThCO- 2-pyridyl

R

7 aCOO 2-ThCO- 3-pyridyl

R

7 aCOO 2-ThCO- 4-pyridyl

R

7 aCOO 2-ThCO- isobutenyl

R

7

,COO

30 2-ThCO- isopropyl

R

7 aCOO 2-ThCO- cyclopropyl

R

7 aCOO- WO 01/57029 PCT/USO1/03600 25 2-ThCO- cyclobutyl

R

7 aCOO 2-ThCO- cyclopentyl

R

7

COO

2-ThCO- phenyl

R

7 aCOO 2-PyCO- 2-furyl

R

7

COO

5 2-PyCO- 3-furyl

R

7 aCOO 2-PyCO- 2-thienyl

R

7

.COO

2-PyCO- 3-thienyl

R

7 aCOO 2-PyCO- 2-pyridyl

R

7

.COO

2-PyCO- 3-pyridyl

R

7 aCOO 10 2-PyCO- 4-pyridyl

R

7 aCOO 2-PyCO- isobutenyl

R

7 aCOO 2-PyCO- isopropyl

R

7 aCOO 2-PyCO- cyclopropyl R 7 aCOO 2-PyCO- cyclobutyl

R

7 aCOO 15 2-PyCO- cyclopentyl

R

7

COO

2-PyCO- phenyl

R

7 aCOO 3-PyCO- 2-furyl

R

7 aCOO 3-PyCO- 3-furyl

R

7 aCOO 3-PyCO- 2-thienyl

R

7 aCOO 20 3-PyCO- 3-thienyl

R

7 aCOO 3-PyCO- 2-pyridyl

R

7 aCOO 3-PyCO- 3-pyridyl

R

7

.COO

3-PyCO- 4-pyridyl

R

7 aCOO 3-PyCO- isobutenyl

R

7 aCOO 25 3-PyCO- isopropyl

R

7

COO

3-PyCO- cyclopropyl

R

7 aCOO 3-PyCO- cyclobutyl

R

7 aCOO 3-PyCO- cyclopentyl

R

7 aCOO 3-PyCO- phenyl

R

7 aCOO 30 4-PyCO- 2-furyl

R

7 aCOO 4-PyCO- 3-furyl R 7 aCOO- WO 01/57029 PCT/USO1/03600 26 4-PyCO- 2-thienyl R 7 aCOO 4-PyCO- 3-thienyl

R

7

,COO

4-PyCO- 2-pyridyl

R

7 aCOO 4-PyCO- 3-pyridyl R 7 aCOO 5 4-PyCO- 4-pyridyl R 7 aCOO 4-PyCO- isobutenyl

R

7 aCOO 4-PyCO- isopropyl R 7 aCOO 4-PyCO- cyclopropyl

R

7 aCOO 4-PyCO- cyclobutyl R 7 aCOO 10 4-PyCO- cyclopentyl

R

7 aCOO 4-PyCO- phenyl

R

7 aCOO

C

4

H

7 CO- 2-furyl R 7 aCOO

C

4

H

7 CO- 3-furyl R 7 aCOO

C

4

H

7 CO- 2-thienyl R 7 aCOO 15 C 4

H

7 CO- 3-thienyl R 7 aCOO

C

4

H

7 CO- 2-pyridyl R 7 aCOO

C

4

H

7 CO- 3-pyridyl R 7 yCOO

C

4

H

7 CO- 4-pyridyl R 7 aCOO

C

4

H

7 CO- isobutenyl R 7 aCOO 20 C 4

H

7 CO- isopropyl

R

7 aCOO

C

4

H

7 CO- cyclopropyl R 7 aCOO

C

4

H

7 CO- cyclobutyl R 7 aCOO

C

4

H

7 CO- cyclopentyl R 7 aCOO 4-PyCO- phenyl R 7 aCOO 25 EtOCO- 2-furyl

R

7 aCOO EtOCO- 3-fu ryl

R

7

COO

EtOCO- 2-thienyl

R

7 aCOO EtOCO- 3-thienyl

R

7 aCOO EtOCO- 2-pyridyl

R

7 aCOO 30 EtOCO- 3-pyridyl R 7 aCOO EtOCO- 4-pyridyl

R

7 aCOO- WO 01/57029 PCT/USO1/03600 27 EtOCO- isobutenyl

R

7 aCOO EtOCO- isopropyl

R

7 aCOO EtOCO- cyclopropyl

R

7 aCOO EtOCO- cyclobutyl R 7 aCOO 5 EtOCO- cyclopentyl

R

7 aCOO EtOCO- phenyl

R

7 aCOO ibueCO- 2-furyl

R

7 aCOO ibueCO- 3-furyl

R

7 aCOO ibueCO- 2-thienyl

R

7 aCOO 10 ibueCO- 3-thienyl R 7 aCOO ibueCO- 2-pyridyl R 7 aCOO ibueCO- 3-pyridyl R 7 aCOO ibueCO- 4-pyridyl

R

7 aCOO ibueCO- isobutenyl

R

7 aCOO 15 ibueCO- isopropyl

R

7 aCOO ibueCO- cyclopropyl

R

7 aCOO ibueCO- cyclobutyl

R

7 aCOO ibueCO- cyclopentyl

R

7 aCOO ibueCO- phenyl R 7 aCOO 20 iBuCO- 2-furyl

R

7 aCOO iBuCO- 3-furyl

R

7 aCOO iBuCO- 2-thienyl

R

7 aCOO iBuCO- 3-thienyl

R

7 aCOO iBuCO- 2-pyridyl R 7 aCOO 25 iBuCO- 3-pyridyl R 7 aCOO iBuCO- 4-pyridyl

R

7 aCOO iBuCO- isobutenyl

R

7 aCOO iBuCO- isopropyl R 7 aCOO iBuCO- cyclopropyl

R

7 aCOO 30 iBuCO- cyclobutyl

R

7 aCOO iBuCO- cyclopentyl 1 RCOO- WO 01/57029 PCT/USO1/03600 28 iBuCO- phenyl

R

7

,COO

iBuOCO- 2-furyl

R

7

COO

iBuOCO- 3-furyl

R

7

.COO

iBuOCO- 2-thienyl

R

7 aCOO 5 iBuOCO- 3-thienyl

R

7

COO

iBuOCO- 2-pyridyl

R

7 aCOO iBuOCO- 3-pyridyl

R

7

COO

iBuOCO- 4-pyridyl

R

7

COO

iBuOCO- isobutenyl

R

7 1COO 10 iBuOCO- isopropyl

R

7 aCOO iBuOCO- cyclopropyl

R

7 aCOO iBuOCO- cyclobutyl

R

7 aCOO iBuOCO- cyclopentyl

R

7 aCOO iBuOCO- phenyl

R

7 aCOO 15 iPrOCO- 2-furyl

R

7 aCOO iPrOCO- 3-furyl

R

7 aCOO iPrOCO- 2-thienyl

R

7 aCOO iPrOCO- 3-thienyl

R

7 1COO iPrOCO- 2-pyridyl

R

7 aCOO 20 iPrOCO- 3-pyridyl

R

7

.COO

iPrOCO- 4-pyridyl

R

7

.COO

iPrOCO- isobuteny

R

7 aCOO iPrOCO- isopropyl

R

7

.COO

iPrOCO- cyclopropyl

R

7 aCOO 25 iPrOCO- cyclobutyl R 7 aCOO iPrOCO- cyclopentyl

R

7

,COO

iPrOCO- phenyl

R

7

,COO

nPrOCO- 2-furyl

R

7 aCOO nPrOCO- 3-furyl

R

7

.COO

30 nPrOCO- 2-thienyl

R

7 aCOO nPrOCO- 3-thienyl I R 7

,COO-

WO 01/57029 PCT/US01/03600 29 nPrOCO- 2-pyridyl

R

7 aCOO nPrOCO- 3-pyridyl

R

7 aCOO nPrOCO- 4-pyridyl

R

7 aCOO nPrOCO- isobutenyl

R

7 aCOO 5 nPrOCO- isopropyl

R

7 aCOO nPrOCO- cyclopropyl

R

7 aCOO nPrOCO- cyclobutyl

R

7 aCOO nPrOCO- cyclopentyl

R

7 aCOO nPrOCO- phenyl

R

7 aCOO 10 nPrCO- 2-furyl

R

7 aCOO nPrCO- 3-furyl

R

7 aCOO nPrCO- 2-thienyl

R

7 aC00 nPrCO- 3-thienyl

R

7

COO

nPrCO- 2-pyridyl

R

7 aCOO 15 nPrCO- 3-pyridyl

R

7 aCOO nPrCO- 4-pyridyl R 7 aCOO nPrCO- isobutenyl

R

7 aCOO nPrCO- isopropyl

R

7 aCOO nPrCO- cyclopropyl

R

7 aCOO 20 nPrCO- cyclobutyl

R

7 aCOO nPrCO- cyclopentyl

R

7 aCOO nPrCO- phenyl R 7 aCOO Example 4 Following the processes described in Example 1 and elsewhere herein, the 25 following specific taxanes having structural formula 15 may be prepared, wherein RIO is hydroxy and R 7 in each of the series (that is, each of series "A" through "K") is as previously defined, including wherein R 7 is R 7 aCOO- wherein R 7 a is a heterosubstituted methyl moiety lacking a carbon atom which is in the beta position relative to the carbon atom of which R 7 a is a substituent. The heterosubstituted A n mp-thvi ic: mnqlantiv hnnelarl to at liaaet n na hotofrnanrm ane ntnfinnoIli/ with hi~rnoion WO 01/57029 PCT/US01/03600 30 the heteroatom being, for example, a nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or halogen atom., The heteroatom may, in turn, be substituted with other atoms to form a heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, oxy, acyloxy, nitro, amino, amido, thiol, ketals, acetals, esters or ether 5 moiety. Exemplary R 7 substituents include R 7 aCOO- wherein R 7 a is hydrogen, methyl, chloromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, phenoxymethyl, acetoxymethyl, acyloxymethyl, or methylthiomethyl. In the "A" series of compounds, X 1 0 is as otherwise as defined herein. Preferably, heterocyclo is substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is 10 substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert butyl), and R 7 and R 1 each have the beta stereochemical configuration. In the "B" series of compounds, X 1 0 and R 2 , are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, 15 phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 and R 1 0 each have the beta stereochemical configuration. In the "C" series of compounds, X 10 and R9a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, 20 thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), Rga is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R, and R 1 each have the beta stereochemical configuration. In the "D" and "E" series of compounds, X 1 0 is as otherwise as defined herein. 25 Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), and R 7 , R 9 (series D only) and R 1 0 each have the beta stereochemical configuration. In the "F" series of compounds, X 1 0 , R 2 a and R 9 a are as otherwise as defined 30 herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R. and R 1 each have the beta stereochemical configuration. 35 In the "G" series of compounds, X 1 0 and R 2 a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, WO 01/57029 PCT/US01/03600 31 thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R. and R 1 0 each have the beta stereochemical configuration. 5 In the "H" series of compounds, X 1 0 is as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 , is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 and R 1 each have the beta stereochemical 10 configuration. In the "I" series of compounds, X 1 0 and R 2 a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or loweralkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, 15 pyridyl, phenyl, or lower alkyl, and R 7 and R 1 each have the beta stereochemical configuration. In the "J" series of compounds, X 1 0 and R 2 a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, 20 phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R. and R 1 each have the beta stereochemical configuration. In the "K" series of compounds, X 10 , R 2 a and R.a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, 25 thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R. and R 1 each have the beta stereochemical configuration. Any substituents of each X 3 , X 5 , R 2 , R 7 , and R. may be hydrocarbyl or any of 30 the heteroatom containing substituents selected from the group consisting of heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester and ether moieties, but not phosphorous containing moieties.

WO 01/57029 PCT/USO1/03600 32

X

5 NH O R OH

R

14 HO

R

2 0 OAc (15) Series X 5 X3 R7 R2 R R14 5 Al -C00X 10 heterocyclo R7,COO- C 6

H

5 COO- 0 H A2 -COX 1 0 heterocyclo R 7 aCOO- CH 5 COO- 0 H A3 -CONHX 1 heterocyclo R 7 ,COO- CHCOO- 0 H A4 -C00X 10 optionally R 7 ,COO- C 6

H

5 COO- 0 H substituted C2 to C8 alkyl A5 -COX 1 0 optionally R 7 aCOO- C 6

H

5 COO- 0 H substituted C2 to C8 alkyl 10 A6 -CONHXO optionally R 7 aCOO- C 6

H

5 COO- 0 H substituted C2 to C8 alkyl A7 -COOX 10 optionally RyCOO- C 6

H

5 COO- 0 H substituted C2 to C8 alkenyl A8 -COX,( optionally R 7 COO- C6H 5 COO- 0 H substituted C2 to C8 alkenyl A9 -CONHXIO optionally RiaCOO- CH 5 COO- 0 H substituted C2 to C8 alkenyl A10 -COOX 1 0 optionally R 7 aCOO- C 6 HCOO- 0 H substituted C2 to C alkynyl 15 Al1 -COX 10 optionally R 7 aCOO- C 6

H

5 COO- 0 H substituted C2 to C alkynyl A12 -CONHX 1 optionally R 7 aCOO- CH 5 COO- 0 H substituted C2 to C alkynyl WO 01/57029 PCT/USO1/03600 33 B1 -COOX 10 heterocyclo R 7 COO- R 2 aCOO- 0 H B2 -COXIo heterocyclo R 7 .COO- R 2 aCOO- 0 H B3 -CONHX,, heterocyclo R 7 COO- R 2 aCO0- 0 H B4 -COOX 1 0 optionally RyCOO- R 2 aCOO- 0 H substituted

C

2 to C, alkyl 5 B5 -COX 1 0 optionally R 7 aCOO- R 2 ,COO- 0 H substituted C2 to C alkyl B6 -CONHXO optionally R 7 aCOO- R 2 ,COO- 0 H substituted C2 to C alkyl B7 -COOX 1 0 optionally R 7 yCOO- R 2 aCOO- 0 H substituted

C

2 to C alkenyl B8 -COX 1 0 optionally R 7 yCOO- R 2 aCOO- 0 H substituted C2 to C alkenyl B9 -CONHXO optionally R 7 aCOO- R 2 aCOO- 0 H substituted C2 to C alkenyl 10 B10 -COOXO optionally R 7 aCOO- R 2 ,COO- 0 H substituted C2 to C alkynyl B11 -COX 10 optionally R 7 aCOO- R 2 aCOO- 0 H substituted C2 to C alkynyl B12 -CONHXO optionally R 7 aCOO- R 2 aCOO- 0 H substituted C2 to C alkynyl ci -COOX 1 0 heterocyclo R 7 COO- C 6

H

5 COO- RgaCOO- H C2 -COXO heterocyclo R 7 COO- C 6

H

5 COO- R 9 aCOO- H 15 C3 -CONHX 1 heterocyclo R 7 aCOO- C 6

H

5 COO- R 9 aCOO- H C4 -COOXO optionally R 7 aCOO- C 6

H

5 COO- RgaCOO- H substituted C2 to C alkyl _____6_____ C5 -COXo optionally RyCOO- C H 5 COO- R 92 COO- H substituted C2 to C alkyl WO 01/57029 PCT/USO1/03600 34 C6 -CONHXIO optionally R7aC0- C6H5COO- R,,COO- H substituted

C

2 to C alkyl C7 -C00X 1 0 optionally RiaCOO- CH 5 COO- R 0,COO- H substituted C2 to C alkenyl C8 -COX 1 0 optionally R 7 aCOO- C 6

H

5 COO- R 0,COO- H substituted C2 to C alkenyl C9 -CONHX 1 optionally R 7 COO- CH COO- R 0,COO- H substituted C2 to C alkenyl 5 C10 -COOX 10 optionally R 7 aCOO- CH 5 COO- R 0,COO- H substituted C2 to C alkynyl C11 -COX 10 optionally R 7 aCOO- C6H 5 COO- R,COO- H substituted C2 to C alkynyl C12 -CONHXO optionally RiaCOO- CHCOO- RgCOO- H substituted C2 to C alkynyl D1 -COOX 1 0 heterocyclo R 7 aCOO- CHCOO- OH H D2 -COX 1 heterocyclo R 7 aCOO- CHCOO- OH H 10 D3 -CONHX 1 heterocyclo R 7 COO- C 8 HCOO- OH H D4 -COOXIO optionally R 7 aCOO- CHCOO- OH H substituted C2 to C alkyl D5 -COX 1 0 optionally R 7 aCOO- CHCOO- OH H substituted C2 to C8 alkyl D6 -CONHXO optionally R 7 aCOO- C6HCOO- OH H substituted C2 to C alkyl D7 -COOX 1 0 optionally R 7 aCOO- CHCOO- OH H substituted C2 to C alkenyl 15 D8 -COX 1 0 optionally R 7 COO- C 6 HCOO- OH H substituted C2 to C, alkenyl D9 -CONHX 1 optionally R 7 yCOO- C 6

H

5 COO- OH H substituted C. -1 to C, alkenyI WO 01/57029 PCT/USO1/03600 35 D10 -COOX 1 0 optionally R 7 aCOO- C 6

H

5 COO- OH H substituted C2 to C alkynyl D11 -COX 1 0 optionally R 7 ,COO- C 6

H

5 COO- OH H substituted C2 to C alkynyl D12 -CONHX 1 optionally R 7 aCOO- C 6

H

5 COO- OH H substituted C2 to C alkynyl El -COOXO heterocyclo R 7 ,COO- C6H 5 COO- 0 OH 5 E2 -COX 1 0 heterocyclo RyaCOO- C 6

H

5 COO- 0 OH E3 -CONHX 1 heterocyclo R 7 aCOO- C 6

H

5 COO- 0 OH E4 -COOX 1 0 optionally R 7 aCOO- C 6

H

5 COO- 0 OH substituted C2 to C. alkyl E5 -COX 1 0 optionally R 7 aCOO- C6H 5 COO- 0 OH substituted C2 to C alkyl E6 -CONHX 1 optionally R 7 aCOO- C 6

H

5 COO- 0 OH substituted C2 to C alkyl 10 E7 -COOX 1 0 optionally R 7 aCOO- C 6

H

5 COO- 0 OH substituted C2 to C alkenyl E8 -COX 1 0 optionally RyCOO- C 6

H

5 COO- 0 OH substituted C2 to C alkenyl E9 -CONHX 10 optionally R 7 ,COO- C 6

H

5 COO- 0 OH substituted C2 to C alkenyl E10 -COOX 1 0 optionally R 7 aCOO- CH 5 COO- 0 OH substituted C2 to C alkynyl El1 -COX 1 0 optionally R 7 aCOO- C 6

H

5 COO- 0 OH substituted C2 to C alkynyl 15 E12 -CONHX 1 e optionally R 7 ,COO- C 6

H

5 COO- 0 OH substituted C2 to C alkynyl Fl -COOX 1 0 heterocyclo RaCOO- R 2 ,COO- RaCOO- H F2 -COX 10 J heterocyclo I R 7 COO- I R 2 aC0 Rg0OO- R H WO 01/57029 PCT/USO1/03600 36 F3 -CONHX 1 heterocyclo R 7 .COO- R 2 ,COO- RgaCOO- H F4 -COOX, optionally R 7 ,COO- R 2 aCOO- RgCOO- H substituted C2 to C alkyl F5 -COX 1 0 optionally R 7 aCOO- R 2 aCOO- R 9 aCOO- H substituted C2 to C alkyl F6 -CONHX,, optionally R 7 aCOO- R 2 aCOO- R 9 COO- H substituted

C

2 to C8 alkyl 5 F7 -COOX 10 optionally R 7 COO- R 2 COO- R 9 aCOO- H substituted C2 to C. alkenyl F8 -COX 1 optionally R 7 COO- R 2 aCOO- RgaCOO- H substituted C2 to C8 alkenyl F9 -CONHXO optionally RiaCOO- R 2 aCOO- R 92 ,C00- H substituted C2 to C8 alkenyl F10 -COOXIO optionally RyCOO- R 2 aCOO- RgCOO- H substituted C2 to C alkynyl F11 -COX 10 optionally R 7 aCOO- R 2 ,COO- R0,COO- H substituted C2 to C alkynyl 10 F12 -CONHXO optionally R 7 aCOO- R 2 aCOO- RgaCOO- H substituted

C

2 to C8 alkynyl G1 -COOXO heterocyclo R 7 aCOO- R 2 aCOO- OH H G2 -COXIO heterocyclo R 7 COO- R 2 aCOO- OH H G3 -CONHX 1 e heterocyclo R 7 aCOO- R 2 aCOO- OH H G4 -COOX 1 e optionally R 7 aCOO- R 2 aCOO- OH H substituted C2 to C alkyl 15 G5 -COX 1 0 optionally RyaCOO- R 2 aCOO- OH H substituted C2 to C8 alkyl G6 -CONHX 1 optionally R 7 COO- R 2 aCOO- OH H substituted C2 to C alkyl WO 01/57029 PCT/USO1/03600 37 G7 -COOX 1 0 optionally R 7 yCOO- R 2 aCOO- OH H substituted C2 to C alkenyl G8 -COX 1 0 optionally R 7 aCOO- R 2 COO- OH H substituted C2 to C alkenyl G9 -CONHX 10 optionally R 7 aCOO- R 2 aCOO- OH H substituted C2 to C alkenyl G10 -COOX 10 optionally R 7 aCOO- R 2 COO- OH H substituted C2 to C alkynyl 5 G11 -COX 1 0 optionally R 7 aCOO- R 2 ,COO- OH H substituted C2 to C alkynyl G12 -CONHX 1 optionally R 7 aCOO- R 2 aCOO- OH H substituted C2 to C alkynyl HI -COOXIO heterocyclo R 7 aCOO- C 6

H

5 COO- OH OH H2 -COX 1 0 heterocyclo R 7 aCOO- CH 5 COO- OH OH H3 -CONHX 1 heterocyclo R 7 aCOO- C6H 5 COO- OH OH 10 H4 -COOX 1 0 optionally R 7 aCOO- C 6

H

5 COO- OH OH substituted C2 to C alkyl H5 -COX 1 0 optionally RaCOO- CH 5 COO- OH OH substituted C2 to C alkyl H6 -CONHX,, optionally R 7 aCOO- C6H 5 COO- OH OH substituted C2 to C alkyl H7 -COOX 10 optionally R 7 aCOO- C 6 HCOO- OH OH substituted C2 to C alkenyl H8 -COX 1 0 optionally R 7 aCOO- C 6 HCOO- OH OH substituted C2 to C alkenyl 15 H9 -CONHXO optionally R 7 aCOO- C 6 HCOO- OH OH substituted C2 to C, alkenyl HIO -COOX 10 optionally R 7 aCOO- CHCOO- OH OH substituted C. I to C 8 alkynyli WO 01/57029 PCT/USO1/03600 38 HI1 -COXIO optionally RyaCOO- C 6

H

5 COO- OH OH substituted C2 to C alkynyl H12 -CONHX 1 optionally R 7 aCOO- C 6

H

5 COO- OH OH substituted C2 to C alkynyl 11 -COOX 1 heterocyclo RaCOO- R 2 aCOO- 0 OH 12 -COXO heterocyclo R 7 aCOO- R 2 aCOO- 0 OH 5 13 -CONHX 1 heterocyclo RaCOO- R 2 aCOO- 0 OH 14 -COOXO optionally RyaCOO- R 2 aCOO- 0 OH substituted C2 to C 8 alkyl 15 -COX 10 optionally RyaCOO- R 2 aCOO- 0 OH substituted C2 to C. alkyl 16 -CONHX 1 optionally R 7 aCOO- R 2 aCOO- 0 OH substituted C2 to C alkyl 17 -COOX 1 0 optionally R 7 aCOO- R 2 COO- 0 OH substituted C2 to C alkenyl 10 18 -COX 1 0 optionally R 7 aCOO- R 2 aCOO- 0 OH substituted C2 to C alkenyl 19 -CONHX 1 optionally R 7 aCOO- R 2 COO- 0 OH substituted C2 to C alkenyl 110 -COOX 1 0 optionally R 7 aCOO- R 2 aCOO- 0 OH substituted C2 to C alkynyl il1 -COX 1 0 optionally R 7 COO- R 2 aCOO- 0 OH substituted C2 to C alkynyl 112 -CONHX 1 e optionally R 7 COO- R 2 COO- 0 OH substituted C2 to C alkynyl 15 J1 -COOX 1 0 heterocyclo R 7 aCOO- R 2 aCOO- OH OH J2 -COX 1 0 heterocyclo RaCOO- R 2 aCOO- OH OH J3 -CONHX 1 , heterocyclo R 7 aCOO- R 2 aCOO- OH OH WO 01/57029 PCT/USO1/03600 39 J4 -COOX 1 0 optionally RyICOO- R 2 aCOO- OH OH substituted C2 to C alkyl J5 -COX 1 optionally R 7 aCOO- R 2 aCOO- OH OH substituted C2 to C alkyl J6 -CONHX 1 0 optionally R 7 aCOO- R 2 aCOO- OH OH substituted

C

2 to C alkyl J7 -COOX 1 optionally R 7 aCOO- R 2 aCOO- OH OH substituted C2 to C, alkenyl 5 J8 -COX 1 0 optionally R 7 aCOO- R 2 aCOO- OH OH substituted C2 to C alkenyl J9 -CONHX 10 optionally R 7 aCOO- R 2 COO- OH OH substituted C2 to C alkenyl J10 -COOX 1 0 optionally R 7 aCOO- R 2 aCOO- OH OH substituted C2 to C alkynyl Ji1 -COX 10 optionally R 7 aCOO- R 2 aCOO- OH OH substituted C2 to C, alkynyl J12 -CONHXO optionally R 7 aCOO- R 2 COO- OH OH substituted C2 to C alkynyl 10 K1 -COOXO heterocyclo R 7 aCOO- R 2 aCOO- R 9 aCOO- OH K2 -COX 1 0 heterocyclo R 7 COO- R 2 aCOO- RgaCOO- OH K3 -CONHX 1 heterocyclo R 7 aCOO- R 2 aCOO- RgaCOO- OH K4 -COOX 1 0 optionally RyaCOO- R 2 .C00- RCOO- OH substituted C2 to C alkyl K5 -COX 10 optionally R 7 COO- R 2 COO- RgaCOO- OH substituted C2 to C alkyl 15 K6 -CONHX 1 optionally R 7 aCOO- R 2 aCOO- RgaCOO- OH substituted C2 to C alkyl K7 -COOX 1 0 optionally R 7 aCOO- R 2 aCOO- R 9 aCOO OH substituted C to C alkenyl WO 01/57029 PCT/USO1/03600 40 K8 -COX 1 0 optionally R 7 aCOO- R 2 aCOO- RgaCOO- OH substituted C2 to C8 alkenyl K9 -CONHX 1 optionally R 7 aCOO- R 2 ,COO- RgaCOO- OH substituted C2 to C alkenyl K10 -COOX 1 optionally R 7 aCOO- R 2 aCOO- RgCOO- OH substituted C2 to C alkynyl K11 -COX 1 0 optionally RyCOO- R2,COO- RgaCOO- OH substituted C2 to C alkynyl 5 K12 -CONHX 1 optionally R 7 aCOO- R 2 aCOO- RCOO- OH substituted C2 to C alkynyl Example 5 In Vitro cytotoxicity measured by the cell colony formation assay Four hundred cells (HCT1 16) were plated in 60 mm Petri dishes containing 2.7 mL of medium (modified McCoy's 5a medium containing 10% fetal bovine serum 10 and 100 units/mL penicillin and 100 g/mL streptomycin). The cells were incubated in a C02 incubator at 37 0C for 5 h for attachment to the bottom of Petri dishes. The compounds identified in Example 2 were made up fresh in medium at ten times the final concentration, and then 0.3 mL of this stock solution was added to the 2.7 mL of medium in the dish. The cells were then incubated with drugs for 72 h at 37 0C. 15 At the end of incubation the drug-containing media were decanted, the dishes were rinsed with 4 mL of Hank's Balance Salt Solution (HBSS), 5 mL of fresh medium was added, and the dishes were returned to the incubator for colony formation. The cell colonies were counted using a colony counter after incubation for 7 days. Cell survival was calculated and the values of ID50 (the drug concentration producing 20 50% inhibition of colony formation) were determined for each tested compound.

WO 01/57029 PCT/US01/03600 41 Compound IN VITRO ID 50 (nm) HCT116 taxol 2.1 docetaxel 0.6 5544 <1 5 5474 <1 5555 <1 5999 <1 6353 <1 6226 <1 10 5622 <1 5515 <1 5445 <1 5600 <1 5616 <1 15 5835 <1 5811 <1 5919 <1 6326 <1

Claims (88)

1. A taxane having the formula: X 5 NH 0 R 10 R 9 X3 0 -, R OH R 14 HO R 2 0 OAc wherein R 2 is acyloxy; R 7 is heterosubstituted acetate; R. is keto, hydroxy, or acyloxy; R 1 is hydroxy; R, 4 is hydrido or hydroxy; X 3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, phenyl or heterocyclo; X 5 is -COX 10 , -C00X 10 , or -CONHX 10 ; X 1 0 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo; and Ac is acetyl.

2. The taxane of claim 1 wherein X 3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C1 - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl.

3. The taxane of claim 1 wherein X 5 is -COX 1 0 and X 1 0 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4 pyridyl, C1 - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl, or X, is -C00X 10 and X 1 0 is substituted or unsubstituted C1 - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl.

4. The taxane of claim 1 wherein X 5 is -COX 1 and X 1 0 is phenyl, or X. is -COOX 1 0 and X 1 0 is t-butyl.

5. The taxane of claim I wherein R 14 is hydrido.

6. The taxane of claim 5 wherein X 3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C1 - C 8 alkyl, C2 - C8 alkenyl, or C2 - C alkynyl. WO 01/57029 PCT/USO1/03600 43

7. The taxane of claim 5 wherein X, is -COX 1 0 and X 1 0 is substituted or unsubstituted phenyl, 2-furyi, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyi, 4 pyridyl, C1 - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl or X 5 is -C00X 1 0 and X 1 0 is substituted or unsubstituted C1 - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl.

8. The taxane of claim 5 wherein X. is -COX 1 0 and X 1 0 is phenyl, or X 5 is -C00X 10 and X 1 0 is t-butyl.

9. The taxane of claim 5 wherein X 3 is phenyl.

10. The taxane of claim 1 wherein R 2 is benzoyloxy.

11. The taxane of claim 10 wherein X 3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C1 - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl.

.12. The taxane of claim 10 wherein X 5 is -COX 1 0 and X 1 0 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4 pyridyl, C1 - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl or X 5 is -C00X 10 and X 1 0 is substituted or unsubstituted C1 - C8 alkyl, C2 - C8 alkenyl, or C2 - C alkynyl.

13. The taxane of claim 10 wherein X 5 is -COX 1 0 and X 1 , is phenyl, or X, is -COOXIO and X 1 0 is t-butyl.

14. The taxane of claim 10 wherein X 3 is phenyl.

15. The taxane of claim 1 wherein R, 4 is hydrido and R. is keto.

16. The taxane of claim 15 wherein X 3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C1 - C8 alkyl, C2 - C alkenyl, or C2 - C8 alkynyl.

17. The taxane of claim 15 wherein X. is -COXIO and X 1 0 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4 pyridyl, C1 - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl or X 5 is -COOX, 0 and X 1 , is substituted or unsubstituted C, - C alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl. WO 01/57029 PCT/USO1/03600 44

18. The taxane of claim 15 wherein X. is -COX 1 0 and X1 0 is phenyl, or X 5 is -C00X 10 and X 1 . is t-butyl.

19. The taxane of claim 15 wherein X 3 is phenyl, and X 5 is -COX 1 0 wherein X 1 0 is phenyl, or X 5 is -C00X 10 wherein X 1 0 is t-butyl.

20. The taxane of claim I wherein R 2 is benzoyloxy and R 9 is keto.

21. The taxane of claim 20 wherein X 3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C1 - C alkyl, C2 - C8 alkenyl, or C2 - C alkynyl.

22. The taxane of claim 20 wherein X. is -COX 1 0 and X 1 0 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4 pyridyl, C1 - C alkyl, C2 - C alkenyl, or C2 - C alkynyl or X 5 is -C00X 10 and X1 0 is substituted or unsubstituted C1 - 08 alkyl, C2 - C alkenyl, or C2 - C alkynyl.

23. The taxane of claim 20 wherein X. is -COXI 0 and X 1 0 is phenyl, or X 5 is -COOX 10 and X 1 0 is t-butyl.

24. The taxane of claim 20 wherein X 3 is phenyl, and X 5 is -COX 1 0 wherein X 1 0 is phenyl, or X 5 is -C00X 10 wherein X 1 0 is t-butyl.

25. The taxane of claim 1 wherein RU is hydrido and R 2 is benzoyloxy.

26. The taxane of claim 25 wherein X 3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C1 - C alkyl, C2 - C alkenyl, or C2 - C alkynyl.

27. The taxane of claim 25 wherein X 5 is -COX 1 0 and X 1 0 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4 pyridyl, C, - C alkyl, C2 - C alkenyl, or C2 - C alkynyl or X, is -C00X 10 and X 1 is substituted or unsubstituted C1 - C alkyl, C2 - C alkenyl, or C2 - C alkynyl.

28. The taxane of claim 25 wherein X, is -COX 1 0 and X 1 0 is phenyl, or X. is -C00X 1 0 and X 1 0 is t-butyl. WO 01/57029 PCT/USO1/03600 45

29. The taxane of claim 25 wherein X 3 is phenyl, and X 5 is -COX 1 wherein X 1 0 is phenyl, or X. is -C00X 10 wherein X 1 0 is t-butyl.

30. The taxane of claim I wherein R 14 is hydrido, R 9 is keto, and R 2 is benzoyloxy.

31. The taxane of claim 30 wherein X 3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C1 - C8 alkyl, C2 - C8 alkenyl, or-C 2 - C8 alkynyl.

32. The taxane of claim 30 wherein X 5 is -COX 1 0 and X 1 0 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4 pyridyl, C1 - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl or X 5 is -C00X 10 and X,, is substituted or unsubstituted C1 - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl.

33. The taxane of claim 30 wherein X. is -COX 1 and X 1 0 is phenyl, or X 5 is -C00X 1 0 and X 1 0 is t-butyl.

34. The taxane of claim 30 wherein X 3 is phenyl, and X, is -COX,, wherein X 1 0 is phenyl, or X. is -C00X 10 wherein X 1 0 is t-butyl.

35. The taxane of claim 30 wherein X, is -C00X 1 0 and X 1 0 is t-butyl.

36. The taxane of claim 35 wherein X. is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, cycloalkyl, alkenyl, or phenyl.

37. The taxane of claim 35 wherein X. is furyl or thienyl.

38. The taxane of claim 35 wherein X 3 is cycloalkyl.

39. The taxane of claim 1 wherein R 7 is R 7 aCOO- and R 7 a is heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, oxy, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester or ether.

40. The taxane of claim 39 wherein R 7 a is heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, or acyloxy. WO 01/57029 PCT/USO1/03600 46

41. The taxane of claim 39 wherein R 7 a is alkoxy, alkenoxy, aryloxy, hydroxy, or acyloxy.

42. A taxane having the formula X 5 NH O R 10 0 X3 tR 7 OH HO BzOAc O R 7 is R 7 aCOO-; 5 Rio is hydroxy; X 3 is substituted orunsubstituted alkyl, alkenyl, alkynyl, phenyl orheterocyclo; X. is -COX 1 0 , -C00X 1 0 , or -CONHX,; X 1 0 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo; and R 7 a is heterosubstituted methyl, said heterosubstituted methyl moiety lacking 10 a carbon atom which is in the beta position relative to the carbon of which R 7 a is a substituent.

43. The taxane of claim 42 wherein X 3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C1 - C alkyl, C2 - C alkenyl, or C2 - C alkynyl.

44. The taxane of claim 43 wherein X 5 is -COX 10 and X 1 0 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4 pyridyi, C, - C alkyl, C2 - C alkenyl, or C2 - C alkynyl, or X. is -COOX 10 and X 1 0 is substituted or unsubstituted C, - C alkyl, C2 - C alkenyl, or C2 - C alkynyl.

45. The taxane of claim 43 wherein R 7 is R 7 aCOO- and R 7 a is heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, oxy, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester or ether, and X 5 is -COXO wherein X 1 0 is phenyl, or X 5 is -COOXO wherein X1 0 is t-butyl. WO 01/57029 PCT/USO1/03600 47

46. The taxane of claim 43 wherein R 7 is R 7 aCOO- and R 7 a is alkoxy, alkenoxy, aryloxy, hydroxy, acyloxy, ester or ether, and X. is -COX 1 0 wherein X 1 0 is phenyl, or X. is -COOXIO wherein X1 0 is t-butyl.

47. The taxane of claim 43 wherein R 7 is R 7 aCOO- and R 7 a is alkoxy, aryloxy, or acyloxy, and X. is -COX1 0 wherein X,, is phenyl, or X 5 is -COOX 1 0 wherein X 1 0 is t-butyl.

48. The taxane of claim 43 wherein X 5 is -COX 1 and X,, is phenyl, or X 5 is -C00X 1 0 and X 1 0 is t-butyl.

49. The taxane of claim 42 wherein X 3 is furyl or thienyl.

50. The taxane of claim 49 wherein X, is -COX 1 0 and X 1 0 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4 pyridyl, C1 - C. alkyl, C2 - C alkenyl, or C2 - C. alkynyl, or X, is -C00X 10 and X,, is substituted or unsubstituted C1 - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl.

51. The taxane of claim 49 wherein X. is -COX 1 0 and X 1 0 is phenyl, or X 5 is -COOXIO and X 1 0 is t-butyl.

52. The taxane of claim 43 wherein X 3 is cycloalkyl.

53. The taxane of claim 52 wherein X. is -COX1 0 and X 1 0 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4 pyridyl, C1 - C8 alkyl, C2 - C8 alkenyl, or C2 - C alkynyl, or X. is -C00X 10 and X 1 0 is substituted or unsubstituted C1 - C8 alkyl, C2 - C8 alkenyl, or C2 - C alkynyl.

54. The taxane of claim 52 wherein X 5 is -COX 1 0 and X 1 0 is phenyl, or X. is -COOX 1 0 and X 1 0 is t-butyl.

55. The taxane of claim 43 wherein X 3 is isobutenyl. WO 01/57029 PCT/USO1/03600 48

56. The taxane of claim 55 wherein X 5 is -COX 1 0 and X 1 , is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4 pyridyl, C1 - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl, or X 5 is -COOX 1 0 and X 1 0 is substituted or unsubstituted C1 - C8 alkyl, C2 - C alkenyl, or C2 - C8 alkynyl.

57. The taxane of claim 55 wherein X. is -COX 1 0 and X 1 0 is phenyl, or X, is -C00X 1 0 and X 1 0 is t-butyl.

58. The taxane of claim 42 wherein R 7 is alkoxyacetyl or acyloxyacetyl.

59. The taxane of claim 58 wherein X 3 is furyl, thienyl, pyridyl, alkyl, alkenyl, or phenyl.

60. The taxane of claim 59 wherein X, is -COX 1 0 and X 1 0 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4 pyridyl, C, - C8 alkyl, C2 - C alkenyl, or C2 - C8 alkynyl, or X 5 is -COOX,, and X 1 is substituted or unsubstituted C1 - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl.

61. The taxane of claim 59 wherein X 5 is -COX 1 0 and X 1 0 is phenyl, or X 5 is -C00X 10 and X 10 is t-butyl.

62. The taxane of claim 58 wherein X 3 is cycloalkyl.

63. The taxane of claim 62 wherein X. is -COX 1 and X 1 0 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4 pyridyl, C1 - C. alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl, or X 5 is -C00X 10 and X 1 0 is substituted or unsubstituted C1 - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl.

64. The taxane of claim 62 wherein X 5 is -COX 1 0 and X 1 0 is phenyl, or X 5 is -C00X 10 and X 1 0 is t-butyl.

65. The taxane of claim 58 wherein X 3 is phenyl. WO 01/57029 PCT/USO1/03600 49

66. The taxane of claim 65 wherein X, is -COX 1 0 and X 1 0 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4 pyridyl, C, - C alkyl, C2 - C alkenyl, or C2 - C alkynyl, or X 5 is -COOX 1 0 and X 0 is substituted or unsubstituted C, - C alkyl, C2 - C alkenyl, or C2 - C alkynyl.

67. The taxane of claim 65 wherein X, is -COX,( and X 1 is phenyl, or X 5 is -C00X 10 and X 1 0 is t-butyl.

68. The taxane of claim 42 wherein X 3 is furyl or thienyl, and X 5 is -COX 1 0 wherein X 1 0 is phenyl, or X, is -COOX1 0 wherein X 1 0 is t-butyl.

69. The taxane of claim 42 wherein X 3 is substituted or unsubstituted furyl, and X. is -COX10 wherein X 1 0 is phenyl, or X, is -C00X 1 0 wherein X 1 0 is t-butyl.

70. The taxane of claim 42 wherein X 3 is substituted or unsubstituted thienyl, and X. is -COX 1 wherein X,, is phenyl, or X, is -COOX, wherein X 10 is t butyl.

71. The taxane of claim 42 wherein X 3 is isobutenyl, and X. is -COX1 0 and X 1 0 is phenyl, or X, is -C00X 1 0 and X 1 0 is t-butyl.

72. The taxane of claim 42 wherein X 3 is alkyl, and X, is -COX 1 0 and X 1 0 is phenyl, or X 5 is -C00X 1 0 and X 1 0 is t-butyl.

73. The taxane of claim 42 wherein X 3 is furyl, thienyl or phenyl, X 5 is -COOX 10 and X 1 0 is t-butyl.

74. The taxane of claim 42 wherein X 3 is isobutenyl or cycloalkyl, X 5 is -C00X 1 0 and X 1 0 is t-butyl.

75. A composition for oral administration comprising the taxane of claim I and at least one pharmaceutically acceptable carrier.

76. The composition of claim 75 wherein X 3 is 2-furyl, 3-furyl, 2-thienyl, 3 thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C1 - C alkyl, C2 - C alkenyl, C2 - C alkynyl, phenyl or substituted phenyl. WO 01/57029 PCT/USO1/03600 50

77. The composition of claim 76 wherein X, is -COX 1 0 and X 1 0 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3 pyridyl, 4-pyridyl, C1 - C8 alkyl, C2 - C alkenyl, or C2 - C alkynyl, or X. is -C00X 10 and X 10 is substituted or unsubstituted C1 - C3 alkyl,C2 - C alkenyl, or C2 -C 8 alkynyl.

78. The composition of claim 76 wherein X 5 is -COX 10 and X 1 is phenyl, or X 5 is -COOX 1 0 and X 1 0 is t-butyl.

79. The composition of claim 76 wherein X 3 is substituted or unsubstituted furyl or thienyl, and X. is -COX 1 0 wherein X 1 0 is phenyl, or X. is -C00X 10 and X 1 0 is t-butyl.

80. A composition for oral administration comprising the taxane of claim 42 and at least one pharmaceutically acceptable carrier.

81. A composition for oral administration comprising the taxane of claim 49 and at least one pharmaceutically acceptable carrier.

82. A method for inhibiting tumor growth in a mammal, said method comprising orally administering a therapeutically effective amount of a pharmaceutical composition comprising the taxane of claim 1 and at least one pharmaceutically acceptable carrier.

83. The method of claim 82 wherein X 3 is 2-furyl, 3-furyl, 2-thienyl, 3 thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C1 - C alkyl, C2 - C alkenyl, C2 - C alkynyl, phenyl or substituted phenyl.

84. The method of claim 83 wherein X 5 is -COX 1 0 and X 1 0 is substituted or unsubstituted phenyl, 2-furyi, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4 pyridyl, C1 - C alkyl, C2 - C alkenyl, or C2 - C alkynyl, or X, is -COOX1 0 and X 1 0 is substituted or unsubstituted C1 - C alkyl, C2 - C alkenyl, or C2 - C alkynyl.

85. The method of claim 83 wherein X, is -COX 1 0 and X 1 0 is phenyl, or X, is -COOX, 0 and X, 0 is t-butyl. WO 01/57029 PCT/USO1/03600 51

86. The method of claim 83 wherein X 3 is substituted or unsubstituted furyl or thienyl, and X. is -COX 1 0 wherein X 1 0 is phenyl, or X, is -COOX 1 0 and X 1 0 is t-butyl.

87. A method of inhibiting tumor growth in a mammal, said method comprising orally administering a therapeutically effective amount of a pharmaceutical composition comprising the taxane of claim 42 and at least one pharmaceutically acceptable carrier.

88. A method of inhibiting tumor growth in a mammal, said method comprising orally administering a therapeutically effective amount of a pharmaceutical composition comprising the taxane of claim 49 and at least one pharmaceutically acceptable carrier.